Ziconotide

Class: Analgesics and Antipyretics, Miscellaneous
VA Class: CN103
Chemical Name: ω-Conotoxin M VIIA
Molecular Formula: C102H172N36O32S7
CAS Number: 107452-89-1
Brands: Prialt

Warning(s)

  • Risk of severe psychiatric symptoms and neurological impairment.1 Do not use in patients with a history of psychosis.1 (See Nervous System Effects under Cautions.)

  • Monitor for cognitive impairment, hallucinations, and changes in mood or consciousness.1

  • Ziconotide therapy can be interrupted or discontinued abruptly without withdrawal effects.1

Introduction

Potent nonopiate analgesic; synthetic conopeptide isolated from venom of the marine snail Conus magus.1 2 3 4 5

Uses for Ziconotide

Severe Chronic Pain

Used intrathecally for relief of severe chronic pain in patients who are intolerant of or do not obtain adequate pain relief from other therapies (e.g., systemic analgesics, adjunctive therapies, intrathecal morphine therapy) when intrathecal therapy is warranted.1 2 3 5

Slideshow: Are You at Risk of Prescription Drug Addiction?

Ziconotide Dosage and Administration

Administration

Administer intrathecally by or under the supervision of a qualified clinician familiar with the drug, the techniques of intrathecal administration, and the device being used.1

Do not administer IV.1

Intrathecal Administration

Administer using a programmable implanted variable-rate microinfusion device (i.e., Medtronic SynchroMed EL or SynchroMed II) or an external microinfusion device and catheter (i.e., CADD-Micro ambulatory infusion pump).1

Consult manufacturer's labeling for specialized administration techniques.1

Consult the manual provided by the manufacturer of the infusion device for specific instructions and precautions for performing a reservoir rinse, initial filling, refilling the reservoir or replacing the drug cartridge, and programming.1

Dilution

Select an appropriate vial strength and final concentration of the drug according to the manufacturer's instructions.1

The commercially available preparation containing ziconotide 25 mcg/mL may be used undiluted.1

The commercially available preparation containing ziconotide 100 mcg/mL may be used undiluted or diluted with preservative-free 0.9% sodium chloride injection prior to placement in the pump.1

Sodium chloride solutions containing preservatives are not appropriate for intrathecal administration and should not be used to dilute ziconotide.1

Initiate infusion of diluted solutions within 24 hours of preparation.1

Dosage

Adults

Severe Chronic Pain
Intrathecal

Initiate using slow dose titration schedule to minimize risk for serious adverse effects.1 (See Common Adverse Effects under Cautions.)

Initially, no more than 2.4 mcg per 24 hours (0.1 mcg/hour).1 Increase dosage based on patient response 2 or 3 times weekly in increments of up to 2.4 mcg per 24 hours (0.1 mcg/hour), up to maximum recommended dosage of 19.2 mcg per 24 hours (0.8 mcg/hour) by day 21.1

Average dosage at day 21 in clinical studies that used the slow titration schedule was 6.9 mcg per 24 hours (0.29 mcg/hour).1

Alternatively, a faster titration schedule can be used if need for urgent analgesia outweighs risk.1 In the fast schedule, dosage is increased daily up to a maximum dosage of 57.6 mcg per 24 hours (2.4 mcg/hr) after 5–6 days.1

Therapy can be interrupted or discontinued abruptly without withdrawal effects.1

Special Populations

Hepatic Impairment

No dosage recommendations.1

Renal Impairment

No dosage recommendations.1

Geriatric Patients

Select dosage with caution, starting at the lower end of the dosage range.1 (See Geriatric Use under Cautions.)

Cautions for Ziconotide

Contraindications

  • Concomitant treatments or medical condition that would make intrathecal administration hazardous (e.g., infection at the microinfusion site, uncontrolled bleeding diathesis, spinal canal obstruction that impairs CSF circulation).1

  • History of psychosis.1

  • Known hypersensitivity to ziconotide or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Nervous System Effects

Acute psychiatric disturbances (e.g., hallucinations, paranoid reactions, hostility, delirium, psychosis, manic reactions) reported.1 Risk may be increased in patients with preexisting psychiatric disorders.1 May cause or worsen depression, resulting in risk of suicide in certain patients.1 If psychiatric disturbances occur, discontinue ziconotide and manage psychosis.1 Careful evaluation needed before reinitiating ziconotide.1

Cognitive impairment (e.g., confusion, memory impairment, speech disorder, aphasia, abnormal thinking, amnesia) reported; generally develops gradually over several weeks and usually is reversible following discontinuance of the drug.1 If cognitive impairment occurs, discontinue or temporarily interrupt ziconotide.1 Consider other causes that may contribute to cognitive impairment.1

Reduced levels of consciousness (e.g., patient is unresponsive or stuporous) reported.1 Increased risk for this adverse effect observed in patients receiving concomitant anticonvulsants, antipsychotics, sedatives, or diuretics.1 If reduced levels of consciousness occurs, discontinue ziconotide until the event resolves; evaluate for other etiologies.1 Discontinue concomitant CNS depressants as clinically appropriate.1

Opiate Withdrawal

Does not prevent or treat the symptoms of opiate withdrawal.1 Avoid withdrawal symptoms in patients discontinuing intrathecal opiate therapy by gradually tapering infusion rate over a few weeks and replacing with equivalent doses of oral opiates.1

Major Toxicities

Meningitis

Meningitis reported rarely; incidence higher in patients with external devices than in those with internal devices.1 May occur secondary to inadvertent contamination of device or from CSF seeding.1

Monitor for signs and symptoms of meningitis (e.g., fever, headache, stiff neck, altered mental status, nausea or vomiting, seizures).1 If meningitis is suspected or confirmed, initiate appropriate measures.1

Prepare doses and fill the drug reservoir under aseptic conditions.1

General Precautions

Serum CK

Possible elevations in CK.1 More likely to occur in men, those receiving antidepressants or anticonvulsants, or those who had received intrathecal morphine.1 Monitor CK concentrations periodically.1 Evaluate patient if neuromuscular symptoms develop.1 If symptoms persist and CK concentrations remain increased or continue to rise, consider dose reduction or drug discontinuation.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known if ziconotide is distributed into milk.1

Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1 6

Geriatric Use

Increased incidence of confusion in patients ≥65 years of age.1 No substantial difference in efficacy relative to younger adults.1

Select dose with caution, starting at the lower end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Common Adverse Effects

Dizziness, nausea, confusion, headache, somnolence, nystagmus, asthenia, pain.1

Serious adverse events and drug discontinuance due to adverse effects occur less frequently when the dosage is increased slowly over 21 days than when a faster dose titration schedule is used.1

Interactions for Ziconotide

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants

Increased risk of elevated serum CK concentrations1

Antidepressants

Increased risk of elevated serum CK concentrations1

CNS depressants

Increased risk of dizziness, confusion, reduced consciousness1

Used concomitantly with anticonvulsants, antidepressants, antipsychotics, anxiolytics, and sedatives in studies1

Dosage adjustment or discontinuance of ziconotide or concomitant CNS depressant may be needed1

Diuretics

Increased risk of reduced consciousness1

Opiates

Previous intrathecal morphine sulfate: Increased risk of elevated serum CK concentrations1

Ziconotide Pharmacokinetics

Absorption

Bioavailability

Intrathecal administration results in little systemic exposure.1

Distribution

Extent

Mean CSF volume of distribution approximates total CSF volume (140 mL).1

Plasma Protein Binding

50%.1

Elimination

Metabolism

Cleaved by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle).1 Minimal hydrolytic activity shown in vitro in CSF and blood.1

Half-life

CSF: 4.6 hours.1

Stability

Storage

Parenteral

Injection

2–8°C; refrigerate during transit.1

Once diluted with preservative-free 0.9% sodium chloride injection, may be stored at 2–8°C for 24 hours.1

Protect from light1

Actions

  • Produces potent antinociceptive effects by selectively binding to N-type voltage-sensitive calcium channels on primary nociceptive afferent nerves in superficial layers of the spinal cord, thus blocking neurotransmission from primary nociceptive afferents.1 2

  • Does not bind to opiate receptors.1 Pharmacologic effects of ziconotide not blocked by opiate antagonists.1 Does not potentiate opiate-induced respiratory depression.1

Advice to Patients

  • Risk of somnolence; avoid driving, operating machinery, or performing hazardous tasks until effects on individual are known.1

  • Importance of informing clinician if new or worsening muscle pain, soreness, weakness, or brown urine develops.1

  • Importance of promptly reporting a change in mental status (e.g., lethargy, confusion, disorientation, decreased alertness), mood or perception (e.g., hallucinations, unusual tactile sensations in the mouth), and symptoms of depression or suicidal ideation.1

  • Importance of promptly informing clinician if symptoms of meningitis (i.e., nausea, vomiting, seizures, fever, headache, stiff neck) occur.1

  • For patients receiving ziconotide via an external microinfusion device and catheter, importance of proper handling of the device and proper care of the skin at the catheter exit site.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1 Potential for additive CNS effects if used concomitantly with other CNS depressants.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ziconotide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for intrathecal administration via compatible microinfusion device only

25 mcg/mL

Prialt

Elan Pharmaceuticals

100 mcg/mL

Prialt

Elan Pharmaceuticals

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Elan Pharmaceuticals. Prialt (ziconotide) intrathecal infusion prescribing information. San Diego, CA; 2005 Feb.

2. Staats PS, Yearwood T, Charapata SG et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004; 291:63-70. [IDIS 509585] [PubMed 14709577]

3. Wermeling D, Drass M, Ellis D et al. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients. J Clin Pharmacol. 2003; 43:624-36. [IDIS 500357] [PubMed 12817525]

4. Atanassoff PG, Hartmannsgruber MW, Thrasher J et al. Ziconotide, a new N-type channel blocker, administered intrathecally for acute postoperative pain. Reg Anesth Pain Med. 2000; 25:274-8. [IDIS 532012] [PubMed 10834782]

5. Doggrell SA. Intrathecal ziconotide for refractory pain. Expert Opin Invest Drugs. 2004; 13:875-7.

6. Elan Pharmaceuticals, San Diego, CA: Personal communication.

Hide
(web1)